I’m excited to announce that our paper finally came out! This was my first corresponding author paper and also my first decision to publish in an open source journal (meaning you should be able to read it for free). This work is the culmination of what I’ve been doing for the past 2 years or so at PHRI as an independent researcher. The patent for it is submitted as well. Things have changed a lot for me very recently and left me wondering where to go with my career. I’m considering branching out on my own and sending applications for PI positions to various places. I’ll keep you all posted on how that process goes as well.

I apologize for holding up my writing this month. I wanted to mention the reason why: it has to do with submitting a patent for one of my projects. I thought this would be a good opportunity to explain a little bit of the process as I’ve experienced it. I had what was almost a 3 hour long conversation with our patent lawyer last week and got a few of the insights into the field of patent law and how it relates specifically to biomolecules. This is the first time I will do this but I feel it needs mentioning: I AM NOT a patent lawyer myself. Though you may like my opinions expressed on this blog please do not take any of what I say here as legal advice.

Patents have always been, and always will be, a source of contention and defensiveness amongst scientists. You can look back to famous examples such as the long patent battles between Thomas Edison and Nikola Tesla for one example (1). Another more recent battle that I’ve brought up before is the fight between The University of California at Berkeley and Harvard University over the rights to CRISPr (2). But perhaps the oldest opponent bioengineers and biochemists have in patent battles is nature itself. Our patent lawyer explained to me that the first hurdle to clear in patenting a molecule is determining whether or not it could be considered “A Product of Nature”. This is to say, to some extent, molecules that exist naturally cannot be patented. Imagine if someone held a patent on the 20 essential amino acids themselves or on the four nucleic acids that make up our DNA! In my non-legal opinion it’s completely unfair to allow someone to try to claim a patent on something our bodies make naturally. The ways to get around this involve, for instance, patenting a process to purify these compounds rather than the compounds themselves. The main point, however, is that to secure a patent you need to make something new or to find a new way to make something old. If you can prove you are not cheating nature then you get the Intellectual Property; you get to decide who makes this produce or uses this process

The power of Intellectual Property and Patent Law has driven the field of synthetic biology, Big Pharma, and yes, even my “Molecular Yoga”. Scripps Research Institute points out, “Natural products remain the best sources of drugs and drug leads, and this remains true today despite the fact that many pharmaceutical companies have deemphasized natural products research in favor of HTP screening of combinatorial libraries during the past 2 decades.” (3). Note their use of the phrase “drugs and drug leads. A drug lead, or more commonly called a lead compound, is a starting point for biomedical researchers. These molecules can be altered and changed to improve the drugs by way of increasing the drug’s binding strength or decreasing side-effects (4). As our patent lawyer pointed out: THAT is what you can patent, as long as you can prove that such changes and alterations were not obvious or already present in small quantities in nature. This is why pharmaceutical companies are focused on screening or rational design of lead compounds; it makes them more easily patentable.

My job, in helping to craft this patent, is to turn what written for an upcoming paper into a set of claims on the patent. Part my discussion last week was determining what we felt we could claim related to our molecules. How, specifically do these molecules work? How are these molecules made? What variations, if any, can exist? Biomolecular patents can have dozens, even hundreds of claims. The goal is to make a patent as broad as possible such that someone cannot easily infringe upon that patent. Would-be infringers might take your molecule and alter it in some nominal way and claim it as their own work. If you can secure a patent with strongly enforceable claims, you can make money off of them through licensing, which will help you fund future research

When I started down the road of becoming a scientist I didn’t make patenting my work one of my main goals. I wanted to create new molecules, things that were useful, but not necessarily things that would make me money. In my opinion, patenting your molecules should be a means to an end, a way to sustain your research. There are a few colleagues of mine who’ve made millions of dollars from patenting simple biomolecules. I imagine it’s hard to prevent yourself from becoming consumed by the drive to make money over the drive to conduct research. They seem to be doing well though. They funnel a lot of that money back into their own lab. This model works especially well for a soft-money driven research facility based on grant-funded rather than tenured positions (something I’d like to go into at a later date). I was involved in creating another patent as a graduate student, which was subsequently accepted as a provisional patent. It appears to me that his work will be heading in that direction as well. I will keep you up to date with my feelings on patents and hopefully this will serve as a good reminder to myself if my views ever change drastically.

Today I wanted to discuss how we see the responsibility of reviewers in science. Peer-review is an integral component of the scientific community. The ability to evaluate and critique the work of others is vitally important in science. I’ve sort of touched on this before when talking about skepticism in science. You can think of a scientific article as an argument that someone is presenting. They need to present the argument as a hypothesis and to defend that hypothesis with their data. At the same time, those reviewing the argument and the data need to be qualified enough to give an informative critique; they need to be peers. I’ll describe what I see as the “modern” style of peer review and then move on to what I see as the “new” style.

The “modern” style of peer review as I would call it has been in use since at least the mid-20th century. Scientific articles had been publish before this time, with editors themselves taking charge of reviewing manuscripts. In the 1950’s and 1960’s academia had grown to such a point where there was both a demand that colleagues be able to review papers in their field before publication and enough qualified people to efficiently outsource the review process (1). In this modern review process, the editor sends out the manuscript to individuals in the field. How these individuals are selected is still somewhat of a mystery to the public at large and, in my opinion, to most of the scientific community as well. Ideally, the reviewers are other scientists who have worked on the same topic or in the same scientific field. The reason for this could be twofold. For one you don’t need to provide as much background information to people already familiar with terms in the article under review, and for two you are much more likely to hold the attention and interests of people who can make connections to their own work.

There is, however, much of the criticism and concern surrounding modern peer-review. In modern peer-review the article authors are not supposed to know their reviewers. This sets up the perverse incentive for someone publishing a similar article to attack competing work unfairly or thwart it’s publication for their own interests. Alternatively, a collaborator might provide very kind review if the paper’s publication might lead to publications for themselves down the line. Most journals have mechanisms to prevent both of these from happening. When submitting an article you are allowed to list a few scientists who “you would not like to be considered for review”. The journal will also mention that you can submit “suggested reviewers” but they cannot be coauthors nor can they be individuals with whom you had professional dealing within the past 4-5 years (e.g. you didn’t write a grant together, you didn’t publish a paper together, you don’t co-advise students etc). These, of course, are just suggestions. The editor gets the final say on picking the reviewers, and they could send it to someone who will give a poor review no matter what. You will not know who the reviewers are during the process and you might never know who reviewed your article. I feel that this modern peer review style is becoming obsolete and that a new peer-review style is emerging.

There is a new style of peer-review emerging since the beginning of the 21st century: Open Review. This type of review has been gaining more mainstream acceptance with the rise of Open-access journals and sites like Publons, which track reviews and reviewer records (2). Under this type of review process everything is out in the open and accessible. All communications between the reviewers and the authors are known and even the identities of the reviewers are known. The content of the reviews will be available along with the article if it is accepted for publication. Additionally there are “post-publication” reviewer, which critique the article after it has been accepted. The goal of this type of review is to demystify the entire process and to facility better discussion about the scholarly merits of an article. The downsides are obvious: there is the threat of collusion, but some studies have shown that there is very little difference in the quality of reviews or the outcome when using an open peer review process as opposed to the more traditional process (3). By opening up the review process we can make the scientific merit of an article stand out even stronger and provide more confidence in the ability of the scientific community to promote good science.

The open peer-review process achieves what I believe should be the main goal of any reviewer: to help improve the scientific merit of an article. The traditional or modern way of thinking about publishing is that it is a battle. In this battle you have been “defeated” if you let a poor article be published so why not err on the side of caution and reject anything that seems even remotely suspect? While I see the value in being a “gate-keeper” as a reviewer I personally feel that stopping there is lazy. The reviewer is responsible for working with an author to improve their article and to strengthen the conclusion they have made about their hypothesis. It would be better to put yourself on the side of the author, to have high standards for yourself, and to ask what your experience and expertise can add to this article to make it a valuable contribution to the journal. With this in mind, open peer-review has to be the best method of fostering the author-reviewer relationship. As a society we seem to be moving ever more and more towards a need for openness and transparency in institutions as well. Having a clear, open review allows gives us confidence in the peer-review process and allows us to sniff out collusion or scientific misconduct. I would encourage everyone to take a look at some articles that have been reviewed under “open peer-review” and to decide for themselves what makes the most sense.

Van Rooyen S. et al. “Effect of open peer review on quality of reviews and on reviewers’ recommendations: a randomized trial” BMJ 1999;318:23

]]>https://molecularyoga.wordpress.com/2017/06/06/reviewer-responsibility/feed/0gwiedmanReadingWhy are People “Rallying Around Science”?https://molecularyoga.wordpress.com/2017/05/02/why-are-people-rallying-around-science/
https://molecularyoga.wordpress.com/2017/05/02/why-are-people-rallying-around-science/#respondTue, 02 May 2017 15:36:01 +0000http://molecularyoga.wordpress.com/?p=140]]>Hello Everyone,

I, like many other scientists, participated in the March for Science this past month. Today I wanted to mention briefly my reasons for participating in the March. There are some good questions being raised in the scientific community about whether or not scientists should be involved in politics or influencing public policy. In my personal, humble, opinion people who think that science is “above politics” are full of themselves. We are all human beings, we all have our own goals and we want to have input on public policy because, by its nature, it affects us. I had the great opportunity last Friday to meet with Dr. Franklin Carrero-Martinez, the Deputy Science and Technology Adviser to the Secretary of State. Dr. Carrero is a scientist by training and one who is now heavily involved in helping the State Department determine what to do with scientific information. This does not mean hiding any information or presenting a biased view but it does mean forming an opinion and making a decision based on a fair reading of the facts. That’s what I was marching for, a fair reading of the facts. In the field of public policy, opinions should not be formed and then backed up with data after the fact. All facts should be debated and an opinion should be formed from that debate. Of course, new data can always help us to refine or even change our opinions. In my mind, however, the failure to form an opinion and failure to take decisive action is a failure in leadership. So again, I’ll call on everyone to please get involved in scientific research and to think about how it affects your daily life.

To add more flexibility to our platforms for conducting scientific research, perhaps it’s time that scientists here in the US take into consideration options abroad. This thought was spurred on by a recent trip I took to China. I had the opportunity to see some of the university system there and how it’s become quite international. Not only can the environment be friendly, but there is also the fact that China is spending the second most total money on R&D behind only the US(1) and has been heavily investing in a computing power that might soon outpace the United States (2). In a previous post I said scientific research is an inherently globalized enterprise. I think as the reputation for quality research increases in Asia this fact will only become clearer. Certainly there are some caveats to working abroad in a large bureaucracy such as China, namely greater amounts of corruption by some academics (3). Still, this is no reason to completely discount the possibility of US students moving outside of the US to conduct their research.

For those seriously considering moving out of the US, it’s important to consider how you’ll be perceived by the scientific community. Students from the US are, by and large, considered top tier in terms of academics. This means students going from the US to, for example, Europe or Asia are very valuable. These students will have some leverage getting a position as a research professor/post doc/grad student abroad. There is always the question, however, of coming back to the United States, if that is the ultimate goal. I haven’t heard much downside to people doing research abroad, especially at top tier universities such as Max Planck, Oxford, University of Tokyo, etc. A person who goes to a smaller institute might be plagued with the same prestige-bias that students who attend smaller universities in the United States suffer. This begs the question: if you want to study or do research at a smaller university, why not try moving abroad?

One last concern about researching abroad, however, is that the research funding systems might work drastically differently in other countries. A labmate from Poland told me that in her country there are barely any postdoc positions available. People either go straight from graduate school to being a professor or not at all. I’ve heard from others that there are similar concerns in other countries in Europe. Certain institutes use a model where the PI of the lab, rather than getting tenure, has a strict term limit for their time. This might the window for what may seem like an ideal position very narrow. Countries such as China strictly limit career movement from university to university. This could cause a problem if the situation in a lab sours. If you are considering moving from the US to another country to do research please do some research into how the academic system works in that country.

Thanks for reading this time. I hope I’ve given you something to think about and maybe at least an interest in looking into how research works in other countries. Regardless of what happens in the world, the pursuit of science will continue to happen all over the Earth. I would encourage you to become a part of it wherever you can!

This month I’ll be attending the 61st Annual Biophysical Society Meeting in New Orleans Louisiana. For some interesting info on Biophysics please check out the blog at: https://biophysicalsociety.wordpress.com/

I’m happy to say that I was able to publish what was the bulk of my PhD thesis work in the Journal of the American Chemical Society and that it is finally available. This work formed the initial basis of my ideas around Molecular Yoga, the ability to control the ways in which molecules can change conformation and activate certain functions. In short, we created a combinatorial library based on the membrane active, toxic peptide Super-Melittin (derived from Melittin from honeybee venom). This peptide has excellent antimicrobial and potent anti-cancer capabilities but it is very harmful to our own body’s cells as well. I believe that by changing just a few of the amino acids we could create a peptide that would be inactive at neutral pH but could fold into an alpha-helix and activate at a low pH. Low pH environments are often found in tumors and with fungi and bacteria, making it an good activating key for these peptides. We’re currently working to develop a patent for these exact purposes and some of my colleagues, Sarah and Elmer are still working very hard to improve these peptides further. Please give it a read and let me know what you think!

I have another announcement too. I’ll be reporting next month as part of the 61st Biophysical Society Meeting blog in New Orleans. I hope to use this as a way to bring science to the public and to help them to interact with the scientific community. Look for updates along these lines in the next few weeks! Thanks for reading!

Before the year is out I wanted to make one last post on a topic I feel is becoming increasingly more important in today’s academic climate. That point is about the difference between skepticism and denial. We hear a lot in the news (fake or real) about how different people are either “deniers” or “skeptics” of various ideas. The utility of vaccines, climate change, AIDS, are just a few topics that come up with these labels on them. Perhaps it would be best to have a discussion of the topic with, instead of politically charged rhetoric, a view towards science itself.

The reason that I’ve been thinking about this topic recently stems from a book I got as part of a Secret Santa gift: “Dancing Naked in the Minefield” by Kerry Mullis. Kerry Mullis won a Nobel Prize for his part in developing Polymerase Chain Reaction synthesis of DNA. He’s a man I deeply disagree with but whom I think has a good point nonetheless. Mullis, in the early 1990’s challenged the prevailing wisdom that Autoimmune Deficiency Syndrome (AIDS) was caused by infection with the Human Immunodeficiency Virus (HIV). By the mid-1990’s, however, there were several cases of isolated HIV accidentally being introduced to healthy individuals and these individuals eventually developing AIDS. These cases established a link between HIV and AIDS(1). For his part, Mullis would describe himself as a “consummate skeptic” always questioning whether or not the scientific community has sufficiently tested and evaluated a hypothesis. In a sense he’s right; as scientists we should always be skeptics, no matter how established the dogma in our field has become. We can go back to Copernicus (and earlier Greeks) challenging the idea that everything revolved around the Earth or Louis Pasteur and others challenging the idea of Spontaneous Generation as examples. There comes a point, however, where to make progress in a field we have to accept that our data point towards a scientific consensus on a topic. From this consensus we can test new hypotheses and create new ideas.

Then we reach what we would call “denial”. Denial, in as non-political of terms as I can put it, is ignoring the scientific consensus and the data that support it and instead interpreting results based on your own biases and beliefs. The correct way to do science is to make as objective observation as possible, create a hypothesis objectively, and then evaluate that hypothesis without presuming any specific outcome. Contrary to popular belief, scientists actually really love to prove things wrong, especially well, established ideas. You have to approach it though as if you don’t already know what is going to happen. A really good scientist will know how to ask new questions regardless of the answer they get. This then gets us into another discussion about transparency in science and the perils of a “results-driven scientific culture” but I’ll get back to that another day. Overall there’s an important difference to highlight: Not all skeptics are deniers but all deniers are bad skeptics.

Finally something to think about for 2017 for both scientists and non-scientists is how we view those in academia and who we look to for authority on a subject. The best defense of the Liberal Arts I ever heard was from a man I greatly admire and respect: Dr. Phil Nichols a professor at the University of Pennsylvania who said (and I’m paraphrasing), “People who study history, language, culture, are the people we turn to when the world is in moral crisis”. People who’ve studied an area very intensely are in unique position to help others understand the world around them. Education is not something to lord over other people like some kind of medieval sale of Indulgences. Rather, it’s a calling and a responsibility; it’s service to humanity at large. Therefore, scientists have a responsibility very clearly communicate what we mean by skepticism and what we mean by scientific consensus.

I wanted to finally post something this month related to science now that the US election is over. A fair warning, this will be another opinion piece of mine; I welcome the opportunity to discuss all manner of opinions.

I, as a scientist in the United States, like many other scientists, apply for funding from the US government. This can come from a number of different places: The National Science Foundation, the National Institutes of Health, the US Department of Energy, US the Department of Defense and many other government sources. There are also outside sources of funding: The Gates Foundation, MacArthur Fellows Program, and The Beckman Foundation all of which provide funding for projects with specific goals in mind. This brings up the obvious question: what sort of bias does receiving funding from a given institute introduce into the scientific process? To address this first point I want to highlight the fact that when scientists apply for a project grant they have already developed a project to fit a specific funding call. From all I can tell faceless government organizations are not handing out projects to push political agendas. Ideas are the currency of the scientific community; few people with good ideas rely on somebody else to pursue them! As scientists we constantly look for new areas to expand the knowledge of the scientific community and we’re always willing to challenge our own views. So while, yes, funding directives might limit the scope of scientific inquiry the scientific community will always look for ways to expand beyond just the easy funding opportunities.

Along this point as well, the scientific community is a global community that goes beyond nationalism. There are nationalistic biases in research as well. People may question the ethics of research done in certain parts of the world or whether or not the results produced there are reliable. I’ve heard people say more than once to take authors’ papers from a particular part of the globe “with a grain of salt.” Still that doesn’t mean that they should be shut out. Their ideas should be put to the test like anyone else’s ideas and if they hold up to scrutiny then they hold up. As scientists from the United States of America we can stick our heads in the sand and say that we are the best and we don’t trust work done outside of the US. This ignores the fact, however, than many other countries are on par or even above our level of R&D spending in terms of per capita GDP. (1) We ought to be proud of the excellent work done in the United States and of the universal respect that the world at large has for US academia. This does not entitle us to narrow our view and miss out on ideas from other parts of the world.

Finally the question that’s been on my mind recently and that I want to discuss is: what is the way forward for the scientific community? What does our global community do in the fact of increased isolationism and reactionary rhetoric throughout the world? I’ll hark back to what I spoke about in previous posts: we need to increase scientific outreach and to help improve public scientific literacy. People would benefit from a better understand of the role that the scientific method plays in their everyday life. They can observe the world around them, make hypotheses about it, test their hypotheses, and analyze the results to come to a logical conclusion. Then, in sharing their conclusions, they will perpetuate a global scientific discourse. This requires all of us to donate our time to reaching out, to teaching the young and the old. Not because we want recognition for it, not because we are afraid of what might happen if we don’t but because we have conviction to do so!

For this post I am going to talk again about drug discovery but in a manner that is really an emerging area of research. The lab I’m working in, though not I personally, have been collaborating with another group at Rockefeller University to study the genomes of the bacteria Rhodococcus equi and R. erythropolis (1). These are bacteria which normally exist in our oral cavities, our nose, and our mouth, but sometimes end up growing in our gut. We’ve talked in a previous post about how changes in your gut microbiome can affect your health. Here, in this paper, we asked the question: what are different types of bacteria doing in your gut and could they actually be useful to us?

Gut bacteria produce all kinds of different molecules that act as signals to your body and towards other bacteria. Your gut is almost like a Wild West of bacteria as well as fungi and viruses, all of which are fighting to survive. When you have the right balance of these organisms you exist in a stable state or “homeostasis”. How do some organisms end up tipping the balance and getting a foothold in the gut? The answer likely comes from the molecules that they produce! Certain types of bacteria might have a way of inhibiting the growth of other bacteria which allows them to overpopulate your gut. We would want to study these bacteria in particular to see what they are doing to our normal homeostasis.

Many of these bacteria are finely tuned to survive in the environment that our bodies provide to them. How can we understand what they are making if we can’t grow enough of them outside of our body? This is where genetics comes in to the picture. We’ve mentioned before one of the central dogmas of biology, that the DNA in a genome encodes for specific protein sequences. Dr. Brady’s lab at Rockefeller looked at the DNA sequences in several portions of the Rhodococcus equi and R. erythropolis genome where we might anticipate active peptides to be encoded. His lab then manually synthesized the peptides that those sequences encoded using synthetic chemistry and tested them against various bacteria and in combination with other drugs called beta lactams (this is the class of drugs that includes Penicillin). They found two active drugs which they called, Humimycins. When they studied these drugs in bacterial culture and when we studied them in mice we discovered that they seem to target a protein complex called a “Flippase”. These Flippases, as the name suggests, have the ability to flip drugs like penicillin to the outside of the cell, thus rendering them ineffective. If you are a bacteria that can inhibit Flippases you can confuse your neighbors and cause dysregulation and you can inhibit their growth.

While this all sounds very exciting there are a few questions that we need to ask about these Humimycins. The first question is: if these drugs are active against specific types of gut bacteria, what effect would using them have on our normal gut microbiome? You might eliminate MRSA for instance but would some other type of bacteria take over your gut? Again this begs the question of what exactly is the “normal” situation in your gut? This is a difficult question and it’s still an area of research that requires an enormous amount of research. For now, because of how difficult beta-lactam resistant bacteria are to deal with, we might as well explore every option we have in our antibiotic arsenal. Overall I think the most encouraging sign is that we are now considering how antibiotics and other drugs affect the microbiome and we are utilizing genetics to try to gain a better understanding of it.

Thanks for reading! I’ve got a few of my own papers in the works so hopefully I’ll be able to discuss it more soon! Cheers!